Engineering Research Center of Cell and Therapeutic Antibody Medicine, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Kobika Institute of Innovative Drug Discovery, School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, 518172, China.
J Neurosci. 2020 Sep 2;40(36):6991-7007. doi: 10.1523/JNEUROSCI.0455-20.2020. Epub 2020 Aug 12.
Pathologic features of Alzheimer's disease (AD) include accumulation of amyloid β (Aβ) and hyperphosphorylated tau protein. We have shown previously that the chemokine-like receptor 1 (CMKLR1) is a functional receptor for Aβ, and CMKLR1 contributes to the uptake of Aβ. However, it is unclear whether CMKLR1 ameliorates or aggravates the process of AD. Here, we show that deletion of the gene coding for CMKLR1 significantly increased Aβ deposits in brains of both male and female amyloid β precursor protein/presenilin-1 mice. However, it markedly decreased the mortality of these mice. Behavioral studies found that CMKLR1 deficiency improved cognitive impairment of male and female amyloid β precursor protein/presenilin-1 mice and intracerebroventricular-streptozotocin injection AD mice. We further explored the effect of CMKLR1 on tau pathology. We found that CMKLR1 deficiency or inhibition attenuated the hyperphosphorylation of tau in brains of AD mice and in the neuronal cells The expression of CMKLR1 on the neurons affected tau phosphorylation by participating in tau seeding. Together, these results uncover a novel mechanism of CMKLR1 in the pathologic process of AD and suggest that inhibiting the promotion effect of CMKLR1 on tau seeding may provide a new strategy for the treatment of AD. Evidence suggests that inflammation is involved in the pathologic progression of AD. The chemokine-like receptor 1 (CMKLR1), belonging to the family of GPCRs, is able to bind and uptake amyloid β. We show here, for the first time, that, although CMKLR1 deficiency increased amyloid β deposits in AD mice, it reduced the mortality and improved the cognitive deficits of AD mice. We furthermore show that CMKLR1 deficiency or inhibition attenuated tau hyperphosphorylation in brains of AD model mice and in neuronal cells Finally, we first discovered that the expression of CMKLR1 on neurons affected tau phosphorylation by participating in tau seeding. These findings suggest that inhibition of CMKLR1 may provide a new strategy for the treatment of AD.
阿尔茨海默病（AD）的病理特征包括淀粉样β（Aβ）的积累和过度磷酸化的tau 蛋白。我们之前已经表明，趋化因子样受体 1（CMKLR1）是 Aβ的功能性受体，并且 CMKLR1有助于 Aβ的摄取。然而，尚不清楚 CMKLR1是否改善或加重 AD 的进程。在这里，我们表明 CMKLR1 基因缺失显著增加了雄性和雌性淀粉样前体蛋白/早老素-1 小鼠大脑中的 Aβ沉积。然而，它显著降低了这些小鼠的死亡率。行为研究发现，CMKLR1 缺乏改善了雄性和雌性淀粉样前体蛋白/早老素-1 小鼠和侧脑室链脲佐菌素注射 AD 小鼠的认知障碍。我们进一步探讨了 CMKLR1 对 tau 病理学的影响。我们发现，CMKLR1 缺乏或抑制减弱了 AD 小鼠大脑中 tau 的过度磷酸化，以及神经元细胞中的 tau 磷酸化。神经元上 CMKLR1 的表达通过参与 tau 播种而影响 tau 磷酸化。总之，这些结果揭示了 CMKLR1 在 AD 病理过程中的新机制，并表明抑制 CMKLR1 对 tau 播种的促进作用可能为 AD 的治疗提供新策略。有证据表明炎症参与了 AD 的病理进展。趋化因子样受体 1（CMKLR1）属于 GPCR 家族，能够结合和摄取淀粉样β。我们在这里首次表明，尽管 CMKLR1 缺乏增加了 AD 小鼠中的 Aβ沉积，但它降低了 AD 小鼠的死亡率并改善了认知缺陷。我们进一步表明，CMKLR1 缺乏或抑制减弱了 AD 模型小鼠大脑中的 tau 过度磷酸化和神经元细胞中的 tau 磷酸化。最后，我们首次发现神经元上 CMKLR1 的表达通过参与 tau 播种而影响 tau 磷酸化。这些发现表明抑制 CMKLR1 可能为 AD 的治疗提供新策略。
